Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Research Involving Thyroid Hormone Lays Foundation for More Targeted Drug Development

25.10.2011
Research led by St. Jude Children’s Research Hospital scientists advances a strategy for taming the side effects and enhancing the therapeutic benefits of steroids and other medications that work by disrupting the activity of certain hormones.

The approach relies on a small molecule developed at St. Jude. In this study, scientists showed that a compound known as SJ-AK selectively blocked the activity of genes in a cell signaling pathway regulated by thyroid hormone.

Investigators showed that SJ-AK also affected cells growing in the laboratory, reducing cell proliferation as well as the production and secretion of a growth hormone regulated by thyroid hormone. The research appears in the October issue of the scientific journal ACS Chemical Biology.

The findings raise hope that compounds like SJ-AK will lead to drugs with more tailored effects by selectively controlling signaling pathways that switch genes on and off. This research focused on a pathway controlled by a thyroid hormone. Investigators said, however, the approach also could potentially be used to target pathways regulated by glucocorticoid, estrogen, androgen and other hormones that are widely used to treat cancer and other conditions but that also have serious side effects.

“This study offers the first evidence it is possible to shut down a portion of the signaling network activated by a particular hormone,” said R. Kiplin Guy, Ph.D., chair of the St. Jude Chemical Biology and Therapeutics Department. Guy is the senior author. The first author is Prabodh Sadana, Ph.D., a former St. Jude postdoctoral fellow who now works in the Department of Pharmaceutical Sciences at Northeastern Ohio Universities College of Medicine and Pharmacy.

Such selectivity could lead to a new generation of medications that promise greater effectiveness and fewer side effects. The new treatments could include steroids that fight leukemia or suppress the inflammation associated with autoimmune disorders without affecting metabolism or bone strength. Small molecules like SJ-AK might aid efforts to develop medicines to control the rapid, life-threatening over-production of a thyroid hormone known as thyroid storm. Guy said the thyroid hormone pathway is also being studied for new opportunities to better regulate obesity or metabolic disease related to cholesterol, triglycerides and fatty acids.

For this study, researchers compared the activity of SJ-AK and NH-3. The compounds use different techniques to target distinct spots in a thyroid hormone signaling pathway.

NH-3 works by competing with a thyroid hormone to bind to the receptor in the cell nucleus. If the hormone wins the competition, the binding starts a biochemical cascade that regulates the activity of genes in the pathway. Those genes produce the proteins that affect growth and other key biological processes. If NH-3 binds to the receptor instead, the impact is like flipping the switch that cuts electricity to the entire building. The entire pathway remains dormant, which is not always desirable.

SJ-AK was developed in Guy’s laboratory. Rather than binding to the hormone receptor like NH-3 does, SJ-AK targets the next step in the pathway. SJ-AK works by displacing proteins called coactivators. Coactivator proteins normally bind to a pocket that is created when a thyroid hormone and receptor bind. As a result, SJ-AK functions like a circuit breaker, selectively blocking parts of the hormone signaling pathway.

In this study, researchers showed that while NH-3 and SJ-AK both target the same signaling pathway and some of the same genes, SJ-AK affects far fewer genes. In laboratory screening tests, researchers found the activity of 193 genes was affected by thyroid hormone. The genes included 79 whose activity was affected by NH-3 and 28 affected by SJ-AK. Investigators showed NH-3 and SJ-AK had little impact on genes outside the thyroid hormone pathways.

Scientists showed NH-3 and SJ-AK also altered the activity of cells. Growth hormone secretion increased 50 percent following the addition of thyroid hormone to human cells growing in the laboratory. When SJ-AK was added, the secretion of growth hormone fell. In another laboratory experiment, researchers reported that both NH-3 and SJ-AK blocked the cell proliferation triggered by growth hormone secretion.

Other authors are Jong Yeon Hwang and Ramy Attia, both formerly of St. Jude; Geoffrey Neale, of St. Jude; and Leggy Arnold of the University of Wisconsin at Milwaukee.

This research was funded in part by the National Institutes of Health and ALSAC.

St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital is internationally recognized for its pioneering research and treatment of children with cancer and other life-threatening diseases. The hospital’s research has helped push overall survival rates for childhood cancer from less than 20 percent when the institution opened to almost 80 percent today. It is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, and no family ever pays St. Jude for care. For more information, visit www.stjude.org.
St. Jude Public Relations Contacts:
Summer Freeman
(desk) 901-595-3061
(cell) 901-297-9861
summer.freeman@stjude.org
Carrie Strehlau
(desk) 901-595-2295
(cell) 901-297-9875
carrie.strehlau@stjude.org

Summer Freeman | Newswise Science News
Further information:
http://www.stjude.org

More articles from Life Sciences:

nachricht A new 'cool' blue
17.01.2020 | American Chemical Society

nachricht Neuromuscular organoid: It’s contracting!
17.01.2020 | Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Miniature double glazing: Material developed which is heat-insulating and heat-conducting at the same time

Styrofoam or copper - both materials have very different properties with regard to their ability to conduct heat. Scientists at the Max Planck Institute for Polymer Research (MPI-P) in Mainz and the University of Bayreuth have now jointly developed and characterized a novel, extremely thin and transparent material that has different thermal conduction properties depending on the direction. While it can conduct heat extremely well in one direction, it shows good thermal insulation in the other direction.

Thermal insulation and thermal conduction play a crucial role in our everyday lives - from computer processors, where it is important to dissipate heat as...

Im Focus: Fraunhofer IAF establishes an application laboratory for quantum sensors

In order to advance the transfer of research developments from the field of quantum sensor technology into industrial applications, an application laboratory is being established at Fraunhofer IAF. This will enable interested companies and especially regional SMEs and start-ups to evaluate the innovation potential of quantum sensors for their specific requirements. Both the state of Baden-Württemberg and the Fraunhofer-Gesellschaft are supporting the four-year project with one million euros each.

The application laboratory is being set up as part of the Fraunhofer lighthouse project »QMag«, short for quantum magnetometry. In this project, researchers...

Im Focus: How Cells Assemble Their Skeleton

Researchers study the formation of microtubules

Microtubules, filamentous structures within the cell, are required for many important processes, including cell division and intracellular transport. A...

Im Focus: World Premiere in Zurich: Machine keeps human livers alive for one week outside of the body

Researchers from the University Hospital Zurich, ETH Zurich, Wyss Zurich and the University of Zurich have developed a machine that repairs injured human livers and keep them alive outside the body for one week. This breakthrough may increase the number of available organs for transplantation saving many lives of patients with severe liver diseases or cancer.

Until now, livers could be stored safely outside the body for only a few hours. With the novel perfusion technology, livers - and even injured livers - can now...

Im Focus: SuperTIGER on its second prowl -- 130,000 feet above Antarctica

A balloon-borne scientific instrument designed to study the origin of cosmic rays is taking its second turn high above the continent of Antarctica three and a half weeks after its launch.

SuperTIGER (Super Trans-Iron Galactic Element Recorder) is designed to measure the rare, heavy elements in cosmic rays that hold clues about their origins...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

11th Advanced Battery Power Conference, March 24-25, 2020 in Münster/Germany

16.01.2020 | Event News

Laser Colloquium Hydrogen LKH2: fast and reliable fuel cell manufacturing

15.01.2020 | Event News

„Advanced Battery Power“- Conference, Contributions are welcome!

07.01.2020 | Event News

 
Latest News

A new 'cool' blue

17.01.2020 | Life Sciences

EU-project SONAR: Better batteries for electricity from renewable energy sources

17.01.2020 | Power and Electrical Engineering

Neuromuscular organoid: It’s contracting!

17.01.2020 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>